ABSTRACT In the United States, several hundred thousand people experience cardiac arrest each year, with the vast majority dying from this condition. Approximately two-thirds of cardiac arrest victims have previously suffered a myocardial infarction (MI), and death results from maladaptive responses to infarct healing. The healed infarct scar creates a substrate that supports malignant ventricular arrhythmias, and death results from ventricular tachycardia (VT) originating in the border zone around the infarct scar. The underlying cellular and tissue electrophysiology that allow the reentrant VT to exist is unknown. Histology studies support a role for surviving ribbons of myocardial tissue traversing the borderzone region, and immunohistochemical studies show decreased connexin expression, implicating impaired electrical conduction as a component of the arrhythmia mechanism. A problem with ascribing causation of VT entirely to these electrical conduction factors is that they occur diffusely throughout the borderzone, but VT exists in discrete circuits. If impaired conduction were sufficient to cause VT, it would come from everywhere within the infarct scar and borderzone, but it does not. Additional factors must be required for existence of VT in the discrete areas where it is found. Our goal is to define the mechanism of post-infarct VT. We have preliminary data showing alterations in KCNE3 expression and action potential duration that are unique to VT circuits. We hypothesize that these repolarization effects combine with the more broadly present alterations in conduction to create conditions that support reentry. To test our hypothesis, we use an integrative, patient-oriented approach with preclinical testing in a clinically relevant large mammalian model of post-infarct VT that we have previously validated for mechanistic and translational studies. We compare the animal model findings to clinical study of patients with post-infarct VT. In that way, we can perform in-depth mechanistic studies in the animal model and then compare the results to the human observations to prove relevance. We will focus on 3 aims: (1) to define the unique anatomical and electrophysiological elements of VT circuits within healed infarct scar in a preclinical model of post-infarction VT, (2) to reverse the maladaptive electrophysiological changes in the healed infarct scar and assess the effects on VT, and (3) to define the unique electrophysiological elements of VT circuits within healed infarct scar in humans. Successful completion of these aims will further our understanding of the mechanism responsible for infarct-related VT, ultimately allowing translation of these findings into novel drug, gene or ablative therapies.